The objective of this proposal is to design and evaluate potential new iron chelating drugs for eventual use in the treatment of patients having iron overload. During the past several years the laboratory has been involved in identifying new compounds with the hopes of finding an orally active drug. Several new classes of drugs have been identified and in the current proposal we hope to take advantage of these findings and develop new drugs. The first drug found was 2,3-dihydroxybenzoic acid which has been found to promote iron excretion following oral administration in iron overloaded rats as well as in patients with B-thalassemia major. Unfortunately the drug is not sufficiently active to be of general use although its oral effectiveness makes it a candidate as an adjunctive chelator. In the current proposal we intend to make derivatives which contain multi-functional dihydroxy benzoyl moietes. It is hoped that these new compounds will be orally absorbed and more effective in vivo. Another class of compounds that we have found to be active following oral administration are acid derivatives of cholic acid. These compounds circulate in the enterohepatic circulation as bile acid analogs and lead to an increased excretion of iron in the stool of iron overloaded rats. In the current proposal we plan to synthesize derivatives containing an additional hydroxamic acid moiety in order to increase the effectiveness of the drug while hopefully retaining its ability to be orally absorbed. In addition a series of other types of molecules having iron binding capabilities will be evaluated. These new compounds will be evaluated in a tissue culture system and an in vivo ironloaded rats. Further work will proceed in identifying the chemical structure of an iron chelating compound isolated from a mammalian liver which facilitates iron transport into Salmonella typhimurium.